ABSTRACT
Full-length antibodies have captured a significant fraction of the sales volume and value of the biopharmaceuticals market.
With increasing knowledge, however, it has been recognized that full-length antibodies may not always be necessary or even
desirable. Antibody fragments provide the opportunity for new therapeutic possibilities. Moreover, antibody fragments have
the potential for simpler, high-yielding production processes, which can translate into a lower manufacturing cost-of-goods
and extended therapeutic benefit. This article discusses the structure and production strategies available for various types
of antibody fragment therapeutics.
Avecia Biologics Ltd.
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With estimated sales of $30 billion in 2007, therapeutic antibodies as a class have validated the effectiveness of using highly
specific binding properties as therapies.1 Most therapeutic antibodies today are full-length IgG molecules because they are structurally stable, have long in vivo half-life and Fc-mediated biological properties. They have a number of drawbacks as therapeutics, however, which include:
- They have high production costs arising from their expression in mammalian cells.
- They are unsuitable for intracellular targets because of their size.
- Binding can be variable depending on the protein targeted (best suited to relatively flat target surfaces).
- Their size can lead to poor tissue penetration arising from their size, which can limit their effectiveness in cases such
as tumor penetration.
- The intellectual property landscape around antibody-based therapeutics discovery and development is complex. Prohibitive "royalty
stacks" often affect the profitability of a resultant drug.
Antibody fragments, on the other hand, can provide highly specific binding as well as a number of therapeutic advantages including:
- flexibility in structure: a diverse range of binding structures can be assembled from antibody-binding domains giving bispecific
or greater binding possibilities per molecule
- enhanced penetration of tissues (particularly of solid tumors) because of their smaller size
- elimination of immunogenicity to the Fc region (fragment structures can be designed without an Fc region)
- simpler production systems. Fragment antibody production is possible with microbial systems such as E. coli and yeasts, translating into lower cost-of-goods (CoGs) and wider application of the benefits of such therapeutic molecules.
Table 1. Examples of antibody fragment products on the market or in development
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The therapeutic effectiveness of antibody fragments has been demonstrated by the licensure of the first antibody fragments.
Genentech's Lucentis, a fragment of Avastin, was approved by the FDA in 2006 and is used for the treatment of wet age-related
macular degeneration.2 In 2008, UCB Pharma's certolizumab pegol (Cimzia), a PEGylated antibody fragment, was approved for the treatment of Crohn's
disease in the US.3 Table 1 shows examples of antibody fragment products that have been launched or are in development. This article discusses
production strategies available for antibody fragment therapeutics.
